Radiotherapy and chemotherapy, alone or combined together with surgery, are essential therapeutic arsenals against human cancer.
Ionizing radiations cause directly or indirectly double-stranded breaks (DSBs) and trigger cell/tissue death (necrosis or apoptosis). The cytotoxic effect of ionizing radiation forms the basis for radiotherapy, which is widely used in the treatment of human cancer. The efficacy of radiotherapy is currently limited by the radio-resistance of certain tumors (for example, glioblastoma, head and neck squamous cell carcinoma) and by the side effects caused by irradiation of nearby normal tissues (for example, in the treatment of breast and cervical cancer).
In the past years, many studies have focused on biological mechanisms related to the ionizing radiation response, in order to gain insights into the complexity of phenomena underlying radio-sensitivity or radio-resistance of tumor cells. The understanding of the different pathways which finely regulate the response to ionizing radiation is an important step towards the identification of molecular targets for new drugs and therapies that, in association with radiotherapy, can improve the chance of recovery from tumors highly resistant to radiation, such as brain or head and neck tumors.
The use of chemotherapeutic agents can cause DNA damages, including direct or indirect DSBs. Examples of mostly used families of chemotherapeutic agents (chemical cytotoxics) are: inhibitors of topoisomerases I or II (camptothecin/topotecan, epirubicin/etoposide), DNA crosslinkers (cisplatin/carboplatin/oxaliplatin), DNA alkylating agents (carmustine/dacarbazine) or anti-metabolic agents (5-fluorouracil/gemcitabine/capecitabine), as well as inhibitors of the mitotic spindles (paclitaxel/docetaxel/vinorelbine).
Recent progress in developing biological drugs (monoclonal antibodies, cytokines/kinase inhibitors, immunotherapies/vaccines) has proven their efficiency and specificity towards a subset of tumors. But they are often used in combination with chemical cytotoxics. Despite of many progresses in the development of new cytotoxic drugs, the drug resistance to chemotherapy is still a major clinical concern in the treatment of cancers. The understanding of the mechanism of drug resistance related to drug uptake/efflux, metabolic degradation, mutagenesis of target enhanced repair, signaling of cell death (apoptosis and necrosis) is essential for insuring efficiency of chemotherapy and improve therapeutic index, especially, in some treatment-resistant tumors.
The association between chemotherapy and radiotherapy was widely used in cancer treatment. Although still not completely elucidated, the biological basis of action of the cytotoxics relies on cellular mechanisms, such as cell cycle or DNA damage, which is also important for the radio-induced cell death, leading to the additive or even better synergistic benefits by combining different treatments in cancer therapies.
In the last decade, many investigations were carried out in this field, and the complexity of signal transduction in response to radiation began to be delineated. In this respect, genes of particular interest to be targeted with ionizing radiations are those involved in the regulation of radiation-induced lethality mechanisms, such as apoptosis or DNA repair. As DSBs are the most lethal DNA damages, the efficacy of ionizing radiation decreases as that of DSB repair increases.
Two mechanisms are involved in the repair of DSBs: non homologous end-joining (NHEJ, sequence-independent pathway) and homologous recombination (HR, sequence-dependent pathway) (reviewed by Jackson, 2002). Targeting genes involved in these two main DSB repair pathways has so far led to little or moderate radio-sensitivity, depending on the used approaches and cancer cell lines (Belenkov et al., 2002; Marangoni et al. 2000; Ohnishi et al, 1998).
Ku (e.g., Ku70 and Ku80) and DNA-PKcs proteins are important in the repair of radiation- or chemo-induced DNA DSBs. If damage cannot be repaired on time, cells die. Therefore, they represent potentially interesting molecular targets for sensitizing target cells and tissues to radiotherapy and chemotherapy. Many approaches have thus been conceived and carried out to try to inhibit these key proteins (Ku70/Ku80, DNA-PKcs, etc.) involved in the NHEJ pathway, which is predominant in mammalian cells:                1) Inhibitors of PI3K (phosphatidylinositol-3-kinase) (i.e., DNA-PKcs, ATM, ATR) (Boulton et al., 2000; Durant & Karran, 2003; Willmore et al., 2004; Vauger et al., 2004);        2) Negative dominant & peptides (C-terminal of KU80) (Marangoni et al., 2000; Kim et al., 2002);        3) Single chain antibody variable fragment (scFv) (DNA-PKcs) (Li et al. 2003);        4) RNA Aptamer (SELEX: RNA binding Ku) (Yoo & Dynan, 1998);        5) Antisense (Ku70, Ku80, DNA-PKcs) (Li et al., 2003b; Marangoni et al., 2000; Sak et al., 2002);        6) siRNA (DNA-PKcs) (Peng et al. 2000).        
Despite these tremendous efforts, the combination of the targeting of genes involved in DNA repair pathways and cancer therapies is still in early experimental stages and no clinical study has shown any proven benefits so far. It is worth to note that the above described approaches share a common feature: they target a single effector (protein) involved in a complex cascade pathway (such as NHEJ) with possible bypass or compensation.